N-substituted lactams



3,459,738 N-SUBSTHTUTED LACTAMS Henri Morren, Forest, Belgium, assignorto UCB (Union Chimique-Chemische Bedrijven), Saint-Gilles-Brussels,Belgium No Drawing. Filed Aug. 3, 1965, Ser. No. 477,004 Claimspriority, application Great Britain, Aug. 6, 1964, 32,037/ 64 Int. Cl.C07d 29/22, 27/08; A611; 25/00 US. Cl. 260-2393 12 Claims ABSTRACT OFTHE DISCLOSURE Compounds of the formula wherein n is 3, 4 or 5, R iswherein m is 1 or 2, and R and R are the same or different, each havingH, alkyl, cycloalkyl, alkenyl, or phenyl, or R and R" together with theN atom, form pyrrolidino, are active in the central nystagmus test butdo not possess antihistamine and/or anticholinergic properties; they aretherefore useful in the treatment of motion sickness and the like whilebeing free from disadvantages generally bound up with antihistamines andanticholerginics (e.g. drowsiness etc.). Methods of preparing thecompounds of the said formula are disclosed.

The present invention relates to new and useful N-substituted lactamsand to the prepartion thereof. The present invention is also related tothe use of these compounds in the therapeutic field, for example, in thetreatment of motion sickness.

Drugs hitherto used for the treatment of motion sickness containantihistamine and/or anticholinergic substances. These drugs are,however, limited in their use because of the side effects which theyproduce, such as somnolence (in the case of antihistamine products),dryness of the mouth and visual disorders (in the case ofantichlolinergic substances) W. J. Oosterveld (Effects on CentralNystagmus, Thesis, Amsterdam, Drukkerij Van Wijk ostzaan (1963), p. 59)has shown that there is a direct relationship betwen activity on centralnystagmus and the activity of drugs useful in the treatment of motionsickness. The central nystagmus test has been described by I. Lackmannet al. (Amer. J. Physiol., 193, (1958), 328-34).

During experiments in this field, I have found that certain compoundspossessing powerful antihistamine and/ or anticholinergic properties arepractically inactive in the central nystagmus test. It is, therefore,assumed that antihistamine and/or anticholinergic properties are neithernecessary nor suflicient to obtain a good drug useful in the treatmentof motion sickness and that a positive test of central nystagmus isneither related to antihistamine nor to anticholinergic activity. Forthis reason, I have tried to discover compounds which, while beingactive in the central nystagmus test, do not possess antihistamineand/or anticholinergic properties and, consequently, do not have thedisadvantages mentioned above.

According to the present invention, I have found that certainN-substituted lactams fully comply with these State Patent 0 conditions.The compounds according to the present invention have, in fact, as greatan activity as that of the best antihistamine and/or anticholinergicsubstances in the central nystagmus test; in addition, they arecompletely without any harmful side effects.

The new compounds of the present invention are N- substituted lactams ofthe formula:

wherein n is an integer of from 3 to 5 and R represents a (CHz)mCONradical in which m is 1 or 2, R and R", which may be same or different,are hydrogen atoms or alkyl, cycloalkyl, alkenyl, alkynyl or phenylradicals, or R and R, together with the nitrogen atom, form aheterocyclic ring, such as pyrrolidine.

The new compounds of the present invention may be prepared, for example,by one of the following processes:

(1) Reaction of the appropriate N-substituted lactam with an alkalimetal hydride to form the corresponding alkali metal derivative, whichis reacted with an appropriate omega-chloroacylamide of the formula inwhich m, R and R have the same meanings as given above, in accordancewith the equation:

Me representing an alkali metal.

(2) Reaction of an appropriate lactam-N-alkanoic acid (when m=1 or 2),with a compound of the formula HN(R')R" in which R and R" have the samemeanings as given above, in accordance with the equation:

32M 2)n 0:0 0:0 \N/ HN(R)R (oflnmoo 0 (lower alkyl (0112),) ON(R')R"Pharmacological tests of the compounds according to the presentinvention have shown that:

(a) The active dose in the rabbit, administered intravenously, is from 2to 4 mg./kg., which corresponds to the doses of antihistamine and/oranticholinergic drugs used for motion sickness, for example scopolaminearzld Z-(benzhydryloxy)-ethyldimethylamine hydrochlon e;

(b) The lethal dose L.D. 50 in the mouse, administered intravenously, ishigher than 10,000 mg./kg., which is a negligible toxicity which isabout times lower than that of ordinary antihistamine and/oranticholinergic drugs;

(c) Antihistamine activity in the guinea-pig is nil;

(d) Atropinic activity in the mouse is nil;

(e) No somnolence is induced in the rabbit, even in .the determinationof the electroencephalogram, for doses up to 3000 mg./kg., administeredintravenously, i.e. 1000 times as great as the practical dose used.

Clinical tests relating to the oral administration of a dose of 200 mg.of one of the compounds of the present invention, namelyN-(2-propyny1)-2-oxo-1-pyrrolidineacetamide, have shown that, of 18persons tested, 16 showed an appreciable decrease of the duration ofnystagmus. The maximum effect observed is obtained 3 hours after theadministration of the product. After hours, the efiect is stillappreciable. The activity on the duration of the nystagmus is,therefore, extremely important.

EXAMPLE 1 N-(Z-propynyl)-2-oxo-l-pipcridineacetamide CHHCONH-CHFCECH 0.2mole of sodium hydride is added to a solution of 0.2 mole ofZ-piperidone in 300 ml. of anhydrous dioxan and the mixture is stirredat room temperature for 15 minutes. It is then heated for 1 hour at 80C.

The mixture is cooled to 200 C. and a solution of 0.2 mole ofN-(Z-propynyl)-chloroacetamide in 300 ml. of anhydrous dioxan is addedslowly. After complete addition, the mixture is heated under reflux for2 hours.

The mixture is hot filtered through Hyflocel and the filtrate evaporatedto dryness. The evaporation residue is taken up in hot ethyl acetate.The product is cooled, filtered through Hyfiocel, the filtrateevaporated and the product distilled. The fraction distilling between160 and and 200 C./0.01 mm. Hg is crystallized in a 5/1 mixture of ethylacetate and hexane.

The resulting compound melts at l03-104 C.

Analysis of the compound for C H N O .Percent N: Calculated, 14.44.Found, 14.54.

N-(2-propynyl)-chloroacetarnide used as starting material was preparedin the following manner:

1 mole of chloroacetyl chloride in 0.5 liter of anhydrous toluene isadded to a solution of 2 moles of 2-propynylamine in 1 liter ofanhydrous toluene, the temperature being maintained below 1 C. Aftercomplete addition, the mixture is stirred for 1 hour at roomtemperature. The mixture is filtered and the solid matter taken up twicewith 500 ml. of hot toluene. The toluene solutions are combined and thenconcentrated to a volume of 300 ml. N-(2-propynyl)-chloroacetamide isobtained in a yield of 80%; M.P. 67-68 C.

Analysis of the compound for C H ClNO.Calculated: N, 10.65%, CI, 27.0%.Found: N, 10.59%; Cl, 27.1%.

EXAMPLE 2 N- (2-propynyl) -hexahydro-2-oxo-azepinel-acetamide N t lHioONH-CHz-CEOH This compound is prepared, according to the method ofExample 1, from hexahydro-2H-azepine-2-one and N-(2-propynyDchloroaoetamide; M.P. 109-1095 C.

Analysis of the compound for C H N O percent N: Calculated, 13.46.Found, 13.53.

EXAMPLE 3 The following compounds were prepared according to theprocedure of Example 1 from 2-oxopyrrolidine and the approriateacetamide:

N -ethyl-2-oxo-l-pyrrolidineacetamide B.P. 130 -140 C./0.01 mm., Hg M.P.8485.5 C.

N-propyl-Z-oxo-l-pyrrolidineacetamide B.P. 155160 C./0.01 mm. Hg

N-allyl-2-oxo-l-pyrrolidineacetamide B.P. 152-156 C./0.01 mm. Hg

N- (2-propynyl -2-oxol-pyrrolidineacetamide M.P. 106-107 C.(crystallized from ethyl acetate)N,N-diethyl-2-oxo-l-pyrrolidineacetamide M.P. 61.5-62.5" C.

EXAMPLE 4 2-oxo-l-pyrrolidineacctamidc (1112C ONE:

A solution of 0.3 mole of ethyl 2-oxo-1-pyrrolidine acetate in 300 ml.of methanol, saturated with ammonia at 20-30 C., is heated at 40-50 C.for 5 hours, while continuously introducing ammonia. The reactionmixture is evaporated to dryness and the residue recrystallized fromisopropanol. 2-oxo-1-pyrrolidine acetamide is obtained in a yield of86%. M.P. 151.5-152.5 C.

Analysis of the compound for C H N O percent N: Calculated, 19.72.Found, 19.71.

2-oxo-1-pyrrolidinepropionamide was also obtained by this process; M.P.142-143 C.

These two compounds have also been prepared according to the procedureof Example 1.

EXAMPLE 5 2-oxo-l-pyrrolidineacetanilide LNL CHQCONH-C} 0.15 mole ofethyl 2-oxo-1-pyrrolidineacetate is added, in an inert atmosphere, to amixture of 0.5 mole of aniline and 0.5 g. of finely divided metallicsodium. After complete addition, the mixtur is slowly heated until thesodium is completely dissolved and then the temperature is raised to C.and kept at that level for 3 hours. ml. of anhydrous toluene are added,the mixture is diluted with hexane until it starts to become cloudy,seed crystals are added and crystallisation occurs. The mixture isfiltered and the solid material recrystallized from ethyl acetate.2-oxo-l-pyrrolidineacetanilide is obtained; M.P. 171- 72 C.

Analysis of the compound for C H N 0 .-percent N: Calculated, 12.84.Found, 12.78.

The following compounds were obtained by the same procedure:

M.P.: 100.5-101.5 C. (crystallized from a 1/1 mixture of ethyl acetateand hexane).

N-cyclohexyl-Z-oxo-l-pyrrolidineacetamide CLO H.CONH C M.P.: 97-98 C.(crystallized from a 1/ 1 mixture of ethyl acetate and hexane).

I claim: 5. N-propyl-Z-oxo-l-pyrrolidineacetamide. 1. A compound of theformula: 6. N-allyl-Z-oxo-l-pyrrolidineacetamide.

(0112) 7. N- 2-pr0pynyl -2-oxo-l-pyrrolidineacetamide. 8.N,N-diethy1-2-oxo-l-pyrrolidineacetarnide.

0:0 9. 2-0Xo-l-pyrrolidineacetamide.

N 5 10. Z-oxo-1-pyrro1idineacetan1l1de.

I 11. 2-oxo-1-pyrrolidineacetopyrrolidide.

wherein n is an integer 1023 to 5, and R is 12.N-cyclohexyl-Z-oxo-l-pyrrolidineacetamide.

/R' 10 References Cited -CH:CON UNITED STATES PATENTS R" 3,250,7845/1966 Gensheimer et a1. 260326.3 and R and R taken separately eachrepresents a mem- 3,185,673 5/ 1965 Aboodber selected from the groupconsisting of hydrogen, lower 3,304,291 2/1967 Dachs et alkyl, loweralkenyl, lower alkynyl, phenyl and cycloalkyl containing 3 to 6 carbonatoms and taken together repre- HENRY LES, Primary Examiner sent withthe adjacent nitrogen atom a pyrrolidine group. R T, BOND, A i tantExaminer 2. N-(Z-propynyl)-2-oxo-l-piperidineacetamide. 3.N-(2-propynyl)-hexahydr0-2-oXo-azepine 1 acet- 20 US. Cl. X.R. amlde-260-326, 294; 424-244, 267, 274

4. N-ethy1-2-oxo-l-pyrrolidineacetamide.

